Fibril-directed Therapies in Systemic Light Chain AL Amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell disorder leading to the production and extracellular deposition of abnormal immunoglobulin light chains called amyloid. The pathogenesis of the disorder is driven by an abnormal plasma cell clone producing excessive monoclonal immunoglobulin light chains, which undergo deposition in various organs of the body such as the heart, kidney, and gastrointestinal tract. The outcome of the disease remains poor, with significant morbidity and mortality associated with the organ dysfunction. The mainstay of therapy remains targeting the plasma cell clone to decrease or eliminate the production of the abnormal light chains. These therapies include agents such as proteasome inhibitors, immunomodulators, and use of autologous stem cell transplantation. Although current therapies offer potential for disease control and improvement in survival, they cannot reverse light chain deposits in the organs. Newer therapies targeting the light chain fibrils in the form of antibodies binding to the amyloid protein in the organ have recently been developed and have shown early efficacy in clinical trials. In this review, we outline the preclinical work, mechanisms of action, and the clinical efficacy of fibril-directed therapies for light chain amyloidosis.